Inhibition of Urinary Bladder Carcinogenesis by Broccoli Sprouts

^{1 1}AgResearch Limited, Ruakura Agricultural Research Center, Hamilton, New Zealand; Departments of ²Pathology and ³Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York; ⁴Institute of Veterinary, Animal and Biomedical Sciences, Massey University, Palmerston North, New Zealand; ⁵The New Zealand Institute for Crop and Food Research Limited, Lincoln, New Zealand; and ⁶Departments of Pharmacology and Molecular Sciences and International Health, the Johns Hopkins University, Baltimore, Maryland

^* To whom correspondence should be addressed. E-mail: yuesheng.zhang{at}roswellpark.org.

	Abstract

Isothiocyanates are a well-known class of cancer chemopreventive agents, and broccoli sprouts are a rich source of several isothiocyanates. We report herein that dietary administration to rats of a freeze-dried aqueous extract of broccoli sprouts significantly and dose-dependently inhibited bladder cancer development induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. The incidence, multiplicity, size, and progression of bladder cancer were all inhibited by the extract, while the extract itself caused no histologic changes in the bladder. Moreover, inhibition of bladder carcinogenesis by the extract was associated with significant induction of glutathione S-transferase and NAD(P)H:quinone oxidoreductase 1 in the bladder, enzymes that are important protectants against oxidants and carcinogens. Isothiocyanates are metabolized to dithiocarbamates in vivo, but dithiocarbamates readily dissociate to isothiocyanates. We found that >70% of the isothiocyanates present in the extract were excreted in the urine as isothiocyanate equivalents (isothiocyanates + dithiocarbamates) in 12 h after a single p.o. dose, indicating high bioavailability and rapid urinary excretion. In addition, the concentrations of isothiocyanate equivalents in the urine of extract-treated rats were 2 to 3 orders of magnitude higher than those in plasma, indicating that the bladder epithelium, the major site of bladder cancer development, is most exposed to p.o. dosed isothiocyanate. Indeed, tissue levels of isothiocyanate equivalents in the bladder were significantly higher than in the liver. In conclusion, broccoli sprout extract is a highly promising substance for bladder cancer prevention and the isothiocyanates in the extract are selectively delivered to the bladder epithelium through urinary excretion. [Cancer Res 2008;68(5):1593–600]

Key Words: Chemoprevention, bladder cancer, sulforaphane, broccoli sprouts, phase 2 enzymes